The goal of this project is to accelerate the translation of low-frequency sine wave stimulation (LFSWS) into a viable clinical therapy for partial onset epilepsy. Although direct electrical brain stimulation is an emerging therapy for the treatment of medically intractable epilepsy, studies to date have reported that less than half of the study subjects have responded to the stimulation parameters tested. LFSWS represents an alternative to the high frequency pulsatile stimulation (HFS) strategies used in focal epilepsy trials. LFSWS is radically different from HFS, which uses short bursts of intermittent high frequency pulses with low charge densities per phase. In contrast, LFSWS uses a continuous low frequency (1 Hz) sine wave with high charge densities per phase and may be delivered in long bursts of up to 90 sec. Animal studies using kindled rats have shown that LFSWS dramatically reduces kindled seizures (Goodman et al., 2005) and increases seizure thresholds (Carrington et al., 2007). Further, the effect of a single treatment on seizure thresholds lasts for many days. No other electrical stimulation strategy has yielded comparable results in this seizure model. However, the effect of LFSWS on spontaneous seizures, the optimization of LFSWS parameters, and the safety of LFSWS have not been fully evaluated. In order to take LFSWS from pre-clinical testing to clinical trials, a team of basic researchers with expertise in animal models of epilepsy, and industry scientists with experience developing neurostimulation therapies for clinical studies, has been assembled. This project encompasses three Specific Aims. The first two aims are devoted to the optimization of LFSWS parameters, and the efficacy and safety testing of LFSWS using the rodent tetanus toxin and pilocarpine spontaneous seizure models. If the preclinical efficacy and safety project milestones are met, preparations will be made to test LFSWS in clinical trials. Thus, the third aim will concentrate on developing prototype clinical neurostimulators and leads for LFSWS, large animal safety testing of the clinical prototypes, the design of the LFSWS clinical trial, and the preparation of FDA and IRB submissions. Public Health Relevance: Direct brain electrical stimulation is an emerging new therapy for the treatment of medically intractable epilepsy, but not all patients have responded to the stimulation strategies tested to date. Low frequency sine wave stimulation dramatically reduces kindled seizures and increases seizure thresholds in rats, and thus represents a potential breakthrough treatment that may bring seizure relief to a broader population of epilepsy patients.